With the advent of modern factor replacement therapy the most important remaining obstacle to successful treatment in haemophilia A is the development of inhibitory antibodies against Facto VIII (FVIII). This retrospective case control study examined genetic variables and early treatment patterns in severe haemophilia A patients who subsequently developed clinically significant inhibitors to FVIII compared with matched controls who did not. Seventy eight inhibitor patients were identified from 13 UK centers over 25 years (1982-2007). For each case an age matched control was selected. Data on potential genetic and treatment related risk factors were collected for cases and controls. Treatment related data was collected for the first 50 exposure days (EDs) for controls or up to inhibitor development for cases. Risk factors were compared for significance by univariate and multivariate analysis. Of the genetic risk factors, major defects in the FVIII gene and non-caucasian ethnicity were each responsible for approximately 5-fold increases in inhibitor risk. When treatment related variables are considered, high intensity treatment increased inhibitor risk around 2.5 fold whether represented by the presence of peak treatment moments or by high overall treatment frequency. This finding was significant regardless of the timing of the high intensity treatment. Periods of intense treatment associated with surgery for porta-cath insertion were however not found to be associated with increased inhibitor risk. No association was shown between inhibitor development and age at first FVIII exposure, type of FVIII product, or the use of regular prophylaxis. This study confirms treatment-related factors as important risks for inhibitor development in Haemophilia A.

Introduction:Nuwiq â (Human-cl rhFVIII) is a new-generation recombinant factor VIII (rFVIII) protein, without chemical modification or fusion to any other protein, produced in a human cell line. Aim/Methods: This prospective, open-label, multinational phase III study assessed the efficacy and safety of Human-cl rhFVIII in 59 previously treated patients (PTPs) with severe haemophilia A aged 2-12 years (2-5 [N = 29]; 6-12 [N = 30]) during standard prophylaxis (≥50 exposure days and ≥6 months). Efficacy in treating breakthrough bleeds and during surgical prophylaxis was also assessed. Results: An initial pharmacokinetic assessment (N = 13 per age subgroup) demonstrated comparable results with the one-stage and chromogenic assays. Mean (SD) half-life was 11.9 (5.4) and 13.1 (2.6) hours in children aged 2-5 years and 6-12 years respectively (one-stage assay). Prophylactic efficacy, based on mean monthly bleeding rate, was 'excellent' or 'good' in 91.5% of children for all bleeds and in 96.6% of children for spontaneous bleeds. Mean (SD) annualized bleeding rate was 4.12 (5.22) [median 1.9] for all bleeds, 1.50 (3.32) [median 0] for spontaneous bleeds and 2.34 (3.54) [median 1.57] for traumatic bleeds. There were no major, life-threatening bleeds. Efficacy was 'excellent' or 'good' in the treatment of 82.4% of breakthrough bleeds. Overall efficacy during five major surgeries was rated as 'excellent'. There were no FVIII inhibitors or treatment-related serious adverse events. Conclusion: These results in paediatric PTPs indicate that Human-cl rhFVIII is effective for the prevention and treatment of bleeds.

Introduction The safety, efficacy and prolonged half‐life of recombinant factor VIII Fc fusion protein (rFVIIIFc) in previously treated patients with severe haemophilia A was demonstrated in the phase 3 A‐LONG and Kids A‐LONG studies. Here, we report interim safety and efficacy data from the rFVIIIFc extension study, ASPIRE (ClinicalTrials.gov #NCT01454739). Methods Eligible subjects could enrol in ASPIRE upon completing A‐LONG or Kids A‐LONG. There were four treatment groups: individualized prophylaxis; weekly prophylaxis; modified prophylaxis (for subjects in whom optimal treatment could not be achieved with individualized or weekly prophylaxis); and episodic treatment. The primary endpoint was development of inhibitors. Results A total of 150 A‐LONG subjects and 61 Kids A‐LONG subjects enrolled in ASPIRE. As of the interim data cut (6 January 2014), the median time on study was 80.9 (A‐LONG) and 23.9 (Kids A‐LONG) weeks. The majority of subjects (A‐LONG, 92.0%; Kids A‐LONG, 57.4%) had ≥100 cumulative rFVIIIFc exposure days. No inhibitors were observed. Adverse events were generally consistent with those expected in the general haemophilia A population. Median annualized bleeding rates (ABRs) were low with individualized [A‐LONG: 0.66; Kids A‐LONG: 0.00 (<6 years old), 1.54 (6 to <12 years old)], weekly (A‐LONG: 2.03) and modified (A‐LONG: 1.97) prophylaxis. There was no change in prophylactic infusion frequency or total weekly prophylactic dose in the majority of subjects from A‐LONG and Kids A‐LONG. Conclusion Interim data from ASPIRE confirm the long‐term safety of rFVIIIFc and the maintenance of a low ABR with extended‐interval prophylactic dosing in patients with severe haemophilia A.

To cite this article: Lawrie AS, Green L, Mackie IJ, Liesner R, Machin SJ, Peyvandi F. Factor XIII -an under diagnosed deficiency -are we using the right assays? J Thromb Haemost 2010; 8: 2478-82.Summary. Background: The clot solubility test is the most widely used method for detection of factor (F)XIII deficiency. However, it will only detect severe deficiencies; consequently mild deficiencies and heterozygous states are probably under diagnosed. Objective: As an alternative first-line screening test, we assessed an automated quantitative ammonia release assay (QARA). Patients/methods: Inter-assay imprecision was evaluated with commercial normal and pathological control plasmas (10 replicates on each of 5 days). Using the QARA and other commercial assays a comparative assessment of congenital (FXIII range < 1-70 u dL, n = 9) and acquired (n = 43) deficiencies was made. We also investigated the prevalence of acquired deficiencies in hospitalized patients using residual samples from adult patients (n = 1004) and from a paediatric intensive care unit (ICU, n = 56). Results: Assay imprecision was acceptably low (normal control: mean 86.6 u dL ), a second chromogenic assay, the FXIII-A and FXIII A+B-subunit ELISA. We found that 21% of samples from adult patients had FXIII levels < 70 u dL )1 (mean normal ± 2 SD 73-161 u dL) with 6% < 50 u dL. Within the paediatric ICU samples, 52% were < 70 u dL . Conclusions: Our data demonstrates that the automated assay is sensitive, highly reproducible and the results from clinical samples suggest that acquired FXIII deficiency is a relatively common phenomenon in hospital patients after surgery and in ICU.

Aims: To undertake a systematic review of the literature reporting the prevalence of thrombophilia in children with a first arterial ischaemic stroke (AIS). Methods: Systematic review of case-control studies reporting data for prevalence of protein C, S, and antithrombin (AT) deficiencies, activated protein C resistance (APCr), total plasma homocysteine .95th centile, the thrombophilic mutations factor V1691 GA, prothrombin 20210GA, and MTHFR C677T in children with first, radiologically confirmed, AIS. Results: Of 1437 potentially relevant citations, 18 met inclusion criteria. A total of 3235 patients and 9019 controls had been studied. Results of meta-analyses were expressed as pooled odds ratios (OR) relating the prevalence of the thrombophilic condition in children with AIS to that in controls. The pooled OR (and 95% CI) were: protein C deficiency, 6.49 (2.96 to 14.27); protein S deficiency, 1.14 (0.34 to 3.80); AT deficiency, 1.02 (0.28 to 3.67); APCr, 1.34 (0.16 to 11.52); FV1691 GA, 1.22 (0.80 to 1.87); PT20210GA, 1.10 (0.51 to 2.34); MTHFR C677T, 1.70 (1.23 to 2.34); and total plasma homocysteine .95th centile, 1.36 (0.53 to 3.51). There was no statistical heterogeneity within these data. Conclusions: All factors examined were more common in children with first AIS than in controls, and significantly so for protein C deficiency and the MTHFR C677T mutation. The implications of thrombophilia for prognosis and recurrence need to be established before clinical recommendations can be made regarding investigation and treatment of children with AIS.